中枢去抑制易化由外周炎症引发大鼠痛敏的机制研究
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摘要
慢性痛是影响最广泛的疾病之一。据估计,在发达国家中约有20%的成年人受到慢性痛的困扰。虽然对急性痛的诊断和治愈目前都很有效,对慢性痛的治疗则远远未达到人们的期望,因此了解慢性痛过程中神经系统是如何作用的就显得尤为迫切。已有的研究表明在慢性痛过程中中枢神经系统中参与痛觉通路的多个脑区的神经元活动增加,突触传递发生变化引起中枢敏化。中枢神经系统痛觉通路的变化是由外周伤害性感受器的输入增多引发,这种变化又导致了参与痛觉信息传递的神经元对外界刺激的反应进一步增强,并且这种增强是一种长时程的变化。研究指出中枢敏化过程中,中枢神经系统的突触传递发生了变化。其中兴奋性突触传递发生了易化,而抑制性突触传递则被抑制。这就提高了兴奋性,使得神经元在接受伤害性刺激时反应增强或是阈下刺激时也会产生反应。
成年动物的中枢神经系统中,GABA能突触传递是主要的快速抑制性突触传递。GABA_A受体是一种氯离子通道,神经元胞内外氯离子浓度梯度决定了它的效能。对多种神经疾病的研究表明神经元上氯离子的转运体KCC2功能受到神经元活动的调节,进而改变抑制性突触传递的效能。此外,GABA的合成酶,GABA能的中间神经元以及GABA_A受体也都受到突触活动的调节,并且在神经疾病中它们的表达与功能也发生变化。虽然已有人证明在外周神经损伤引起的慢性痛过程中也存在着抑制性突触传递的降低(去抑制),然而对这种降低的机制研究还不够深入。本研究中,我们利用外周炎症引起的慢性痛成年大鼠模型,对抑制性系统在中枢痛觉通路的多个脑区的变化进行了研究,并探索了调节抑制性突触传递的可能生理意义。
1.慢性炎症痛大鼠脊髓背角KCC2的表达变化与其机制的研究
本研究中,我们发现在外周炎症诱发的慢性痛过程中,脊髓背角浅层神经元的KCC2表达明显降低,并且这种降低呈现时间依赖关系,随着慢性痛持续时间的延长,KCC2的表达持续降低。KCC2的表达降低起到了易化痛敏的作用。此外,单侧的外周炎症会引起双侧脊髓背角的KCC2表达降低。我们也证明慢性炎症痛中KCC2的降低依赖于BDNF-TrkB受体信号通路的激活。我们的研究结果提示,在外周炎症诱发的慢性痛过程中脊髓背角也会出现去抑制,KCC2降低易化痛敏的机制可能是减少神经元胞内外的氯离子梯度,降低了抑制性突触传递的效能。而KCC表达降低的时间依赖性则提示其降低可能对慢性痛的维持贡献更大。而KCC2的降低是由BDNF-TrkB受体信号通路的激活所导致的,这也说明KCC2的表达受到神经元活动的调节。
2.前扣带回皮层的去抑制易化了慢性痛中的痛敏的研究
本研究中,我们利用全细胞膜片钳的方法首先检测了外周炎症诱发的慢性痛对前扣带皮层Ⅱ,Ⅲ层神经元上兴奋性突触传递的影响。我们发现慢性痛导致了这些神经元的兴奋性输入增多。另一方面,这些神经元接受的抑制性突触传递则发生了显著降低。我们进一步对抑制性突触传递降低的机制进行了探索。通过对mIPSC进行非稳态噪音分析,我们发现在突触传递过程中被激活的GABA_A受体数量减少,同时通过配对刺激记录IPSC,我们发现在慢性痛中抑制性突触的突触前释放机制发生了变化但释放概率没有降低,这就提示我们观察到的抑制性突触传递的降低可能主要是由于突触后受体减少造成的。通过检测GABA_A受体的β2,3亚基在前扣带回皮层的表达我们发现外周炎症诱发的慢性痛降低了GABA_A受体在前扣带回皮层的表达,KCC2的表达也降低。另一方面,负责合成GABA的谷氨酸脱羧酶的表达并没有降低,GAD65的表达反而在慢性痛中上升。此外,外周炎症诱发的慢性痛引起前扣带皮层神经元的输出增加并且我们的结果提示这些神经元对兴奋性输入的整合发生变化。行为学实验则提示,慢性痛中增强前扣带皮层抑制性突触传递可以减缓痛敏。因此,本研究提示,前扣带回皮层的抑制性突触传递的降低易化了慢性痛中痛敏,这种降低是由于GABA_A受体和KCC2的表达降低引起的。而与此同时,前扣带回皮层的抑制性系统也可能存在着稳态调节机制试图弥补受体表达降低导致的抑制性突触传递的削弱。增高的兴奋性与降低的抑制性输入就导致了神经元的输出增加。
本工作的创新在于:1)第一次报道了外周炎症诱发的慢性痛会导致KCC2的表达长时程下调,并且这种下调依赖于BDNF-TrkB受体信号途径的激活。这就提示了KCC2表达降低可能是对多种慢性痛的维持起重要作用。2)第一次报道了外周炎症诱发的慢性痛会导致前扣带回皮层抑制性突触传递的降低,这种降低促进了了神经元的输出,易化了痛敏。并且我们也证明在慢性痛中前扣带回皮层抑制性系统存在稳态调节机制。
Chronic pain is one of the largest medical health problems. It affects approximately 20% of the adult population. While the management and treatment of acute pain is reasonably good, the needs of patients suffering chronic pain are largely unmet. Thus it is an urgent task for researchers to understand the role of central nervous system during chronic pain. Studies have shown that multiple brain regions in the central pain pathway endured long-term activity change during chronic pain, and the enhanced excitatory neurotransmission in these regions contributes to central sensitization. The change in central pain pathway is induced by increased input form peripheral nociceptors, and the change leads to long-term increased output of the neurons to noxious stimuli and stimuli which normally never produce pain.
GABAergic transmission is the major fast inhibitory transmission in the central nervous system of adult mammals. As the GABA_A receptor is a chloride-permeable channel, its efficacy is largely determined by chloride gradient. Many studies shown that one of chloride transporters, Potassium-Chloride Co-Transporter (KCC2) endured decreased during many psychological diseases and abnormal synaptic activity, and the efficacy of GABAergic transmission decreased due to increased intracellular chloride concentration. Further more, synaptic activity change and psychological diseases also can lead to changes of GABA synthase, GABAergic interneuron, and GABA_Areceptors, as suggested by many studies. It is possible that decreased inhibitory transmission (disinhibition) is a general theme during abnormal brain activity. Recent advances suggest that peripheral nerve injury leads to disinhibition in central pain pathway; however, the mechanism of disinhibition is not fully investigated. In the present study, we investigated inhibitory transmission in brain regions involved in central pain pathway of rats suffering chronic pain induced be peripheral inflammation, and studied mechanism which lead to disinhibition.
In the present study, we showed that:
1. Reduced KCC2 Expression in Spinal Cord Dorsal Horn Neurons Contributes to Inflammatory Pain Hypersensitivity in Rats. In this part of study, we found the expression of KCC2 endured continuous decreased in the dorsal horn of spinal cord after peripheral inflammation, and the decrease contributed to hyperalgesia during chronic pain. The contralateral side to inflammation was also observed with decreased KCC2 expression. We further showed that KCC2 in the superficial layers of the dorsal horn suffered most. Further more, we found activation of BDNF-TrkB signaling pathway is necessary for KCC2 decrease. These results suggest that during peripheral inflammation, KCC2 expression also reduced, and such a decrease probably contributes to the maintenance of chronic pain. The role of BDNF-TrkB pathway on KCC2 expression also suggests that KCC2 expression is regulated by neuronal activity.
2. Disinhibition in anterior cingulate cortex (ACC) contributes to hyperalgesia. We showed in this part of study that peripheral inflammation induced chronic pain increased excitatory transmission in ACC, and decreased inhibitory transmission. Using non-stationary fluctuation analysis, we found that activated GABA_Areceptor number in mIPSC event decreased after peripheral inflammation. Recording of paired-pulse IPSCs showed that the presynaptic mechanism of GABAergic transmission also altered, as the release probability increased. Thus our data suggest that reduced postsynaptic GABA_A receptor is more likely to contribute to disinhibition. We further confirmed this as the expression of GABA_a receptorβ2/3 subunits decreased while GABA synthase GAD65 increased. These results also suggest that a homeostasis regulation of GABAergic transmission also occurred during disinhibition. We further showed that disinhibition altered firing of ACC neurons, which might underlie the mechanism of spontaneous pain, observed in chronic pain patients. Behavioral study of chronic pain rats showed that disinhibition contributed to hyperalgesia.
In this study we first time demonstrated during peripheral inflammation induced chronic pain KCC2 in the dorsal horn endured long-term decrease, which is induced by BDNF-TrkB signaling pathway activation. This suggests that reduced KCC2 in the dorsal horn could be a general theme in chronic pain. We also first time demonstrated that peripheral inflammation induced chronic pain would lead to disinhibition in anterior cingulate cortex. The disinhibition increased out put of ACC neurons, and facilitated hyperalgesia. Further more we also showed that homeostasis compensation of GABAergic transmission occur during inhibition.
成年动物的中枢神经系统中,GABA能突触传递是主要的快速抑制性突触传递。GABA_A受体是一种氯离子通道,神经元胞内外氯离子浓度梯度决定了它的效能。对多种神经疾病的研究表明神经元上氯离子的转运体KCC2功能受到神经元活动的调节,进而改变抑制性突触传递的效能。此外,GABA的合成酶,GABA能的中间神经元以及GABA_A受体也都受到突触活动的调节,并且在神经疾病中它们的表达与功能也发生变化。虽然已有人证明在外周神经损伤引起的慢性痛过程中也存在着抑制性突触传递的降低(去抑制),然而对这种降低的机制研究还不够深入。本研究中,我们利用外周炎症引起的慢性痛成年大鼠模型,对抑制性系统在中枢痛觉通路的多个脑区的变化进行了研究,并探索了调节抑制性突触传递的可能生理意义。
1.慢性炎症痛大鼠脊髓背角KCC2的表达变化与其机制的研究
本研究中,我们发现在外周炎症诱发的慢性痛过程中,脊髓背角浅层神经元的KCC2表达明显降低,并且这种降低呈现时间依赖关系,随着慢性痛持续时间的延长,KCC2的表达持续降低。KCC2的表达降低起到了易化痛敏的作用。此外,单侧的外周炎症会引起双侧脊髓背角的KCC2表达降低。我们也证明慢性炎症痛中KCC2的降低依赖于BDNF-TrkB受体信号通路的激活。我们的研究结果提示,在外周炎症诱发的慢性痛过程中脊髓背角也会出现去抑制,KCC2降低易化痛敏的机制可能是减少神经元胞内外的氯离子梯度,降低了抑制性突触传递的效能。而KCC表达降低的时间依赖性则提示其降低可能对慢性痛的维持贡献更大。而KCC2的降低是由BDNF-TrkB受体信号通路的激活所导致的,这也说明KCC2的表达受到神经元活动的调节。
2.前扣带回皮层的去抑制易化了慢性痛中的痛敏的研究
本研究中,我们利用全细胞膜片钳的方法首先检测了外周炎症诱发的慢性痛对前扣带皮层Ⅱ,Ⅲ层神经元上兴奋性突触传递的影响。我们发现慢性痛导致了这些神经元的兴奋性输入增多。另一方面,这些神经元接受的抑制性突触传递则发生了显著降低。我们进一步对抑制性突触传递降低的机制进行了探索。通过对mIPSC进行非稳态噪音分析,我们发现在突触传递过程中被激活的GABA_A受体数量减少,同时通过配对刺激记录IPSC,我们发现在慢性痛中抑制性突触的突触前释放机制发生了变化但释放概率没有降低,这就提示我们观察到的抑制性突触传递的降低可能主要是由于突触后受体减少造成的。通过检测GABA_A受体的β2,3亚基在前扣带回皮层的表达我们发现外周炎症诱发的慢性痛降低了GABA_A受体在前扣带回皮层的表达,KCC2的表达也降低。另一方面,负责合成GABA的谷氨酸脱羧酶的表达并没有降低,GAD65的表达反而在慢性痛中上升。此外,外周炎症诱发的慢性痛引起前扣带皮层神经元的输出增加并且我们的结果提示这些神经元对兴奋性输入的整合发生变化。行为学实验则提示,慢性痛中增强前扣带皮层抑制性突触传递可以减缓痛敏。因此,本研究提示,前扣带回皮层的抑制性突触传递的降低易化了慢性痛中痛敏,这种降低是由于GABA_A受体和KCC2的表达降低引起的。而与此同时,前扣带回皮层的抑制性系统也可能存在着稳态调节机制试图弥补受体表达降低导致的抑制性突触传递的削弱。增高的兴奋性与降低的抑制性输入就导致了神经元的输出增加。
本工作的创新在于:1)第一次报道了外周炎症诱发的慢性痛会导致KCC2的表达长时程下调,并且这种下调依赖于BDNF-TrkB受体信号途径的激活。这就提示了KCC2表达降低可能是对多种慢性痛的维持起重要作用。2)第一次报道了外周炎症诱发的慢性痛会导致前扣带回皮层抑制性突触传递的降低,这种降低促进了了神经元的输出,易化了痛敏。并且我们也证明在慢性痛中前扣带回皮层抑制性系统存在稳态调节机制。
Chronic pain is one of the largest medical health problems. It affects approximately 20% of the adult population. While the management and treatment of acute pain is reasonably good, the needs of patients suffering chronic pain are largely unmet. Thus it is an urgent task for researchers to understand the role of central nervous system during chronic pain. Studies have shown that multiple brain regions in the central pain pathway endured long-term activity change during chronic pain, and the enhanced excitatory neurotransmission in these regions contributes to central sensitization. The change in central pain pathway is induced by increased input form peripheral nociceptors, and the change leads to long-term increased output of the neurons to noxious stimuli and stimuli which normally never produce pain.
GABAergic transmission is the major fast inhibitory transmission in the central nervous system of adult mammals. As the GABA_A receptor is a chloride-permeable channel, its efficacy is largely determined by chloride gradient. Many studies shown that one of chloride transporters, Potassium-Chloride Co-Transporter (KCC2) endured decreased during many psychological diseases and abnormal synaptic activity, and the efficacy of GABAergic transmission decreased due to increased intracellular chloride concentration. Further more, synaptic activity change and psychological diseases also can lead to changes of GABA synthase, GABAergic interneuron, and GABA_Areceptors, as suggested by many studies. It is possible that decreased inhibitory transmission (disinhibition) is a general theme during abnormal brain activity. Recent advances suggest that peripheral nerve injury leads to disinhibition in central pain pathway; however, the mechanism of disinhibition is not fully investigated. In the present study, we investigated inhibitory transmission in brain regions involved in central pain pathway of rats suffering chronic pain induced be peripheral inflammation, and studied mechanism which lead to disinhibition.
In the present study, we showed that:
1. Reduced KCC2 Expression in Spinal Cord Dorsal Horn Neurons Contributes to Inflammatory Pain Hypersensitivity in Rats. In this part of study, we found the expression of KCC2 endured continuous decreased in the dorsal horn of spinal cord after peripheral inflammation, and the decrease contributed to hyperalgesia during chronic pain. The contralateral side to inflammation was also observed with decreased KCC2 expression. We further showed that KCC2 in the superficial layers of the dorsal horn suffered most. Further more, we found activation of BDNF-TrkB signaling pathway is necessary for KCC2 decrease. These results suggest that during peripheral inflammation, KCC2 expression also reduced, and such a decrease probably contributes to the maintenance of chronic pain. The role of BDNF-TrkB pathway on KCC2 expression also suggests that KCC2 expression is regulated by neuronal activity.
2. Disinhibition in anterior cingulate cortex (ACC) contributes to hyperalgesia. We showed in this part of study that peripheral inflammation induced chronic pain increased excitatory transmission in ACC, and decreased inhibitory transmission. Using non-stationary fluctuation analysis, we found that activated GABA_Areceptor number in mIPSC event decreased after peripheral inflammation. Recording of paired-pulse IPSCs showed that the presynaptic mechanism of GABAergic transmission also altered, as the release probability increased. Thus our data suggest that reduced postsynaptic GABA_A receptor is more likely to contribute to disinhibition. We further confirmed this as the expression of GABA_a receptorβ2/3 subunits decreased while GABA synthase GAD65 increased. These results also suggest that a homeostasis regulation of GABAergic transmission also occurred during disinhibition. We further showed that disinhibition altered firing of ACC neurons, which might underlie the mechanism of spontaneous pain, observed in chronic pain patients. Behavioral study of chronic pain rats showed that disinhibition contributed to hyperalgesia.
In this study we first time demonstrated during peripheral inflammation induced chronic pain KCC2 in the dorsal horn endured long-term decrease, which is induced by BDNF-TrkB signaling pathway activation. This suggests that reduced KCC2 in the dorsal horn could be a general theme in chronic pain. We also first time demonstrated that peripheral inflammation induced chronic pain would lead to disinhibition in anterior cingulate cortex. The disinhibition increased out put of ACC neurons, and facilitated hyperalgesia. Further more we also showed that homeostasis compensation of GABAergic transmission occur during inhibition.
引文
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